Tuberculosis (TB) is a contagious disease caused predominantly by a bacterium called Mycobacterium tuberculosis. The bacteria mostly attack the lungs (pulmonary TB), but they can also attack the spine, brain, kidneys, and other organs or tissues. If not treated properly, TB can be fatal. There are 9.2 million new cases and 1.7 million deaths from TB annually. In addition, these intracellular bacteria are responsible for millions of cases of leprosy. Other debilitating diseases transmitted predominantly by intracellular agents include cutaneous and visceral leishmaniasis, American trypanosomiasis (Chagas disease), malaria, listeriosis, toxoplasmosis, histoplasmosis, trachoma, psittacosis, Q-fever, and Legionellosis including Legionnaires' disease. At this time, relatively little can be done to prevent debilitating infections in susceptible individuals exposed to these organisms. The first-diagnosed Mycobacterium tuberculosis infection is curable with the first line of anti-tuberculosis drugs (ATT) in over 90% of cases within 6 months.
However, when TB presents with HIV or there is a relapsing TB or drug-resistant form of TB, such as multi-drug resistant TB (MDR-TB) or extensively-drug resistant TB (XDR-TB), the currently available drugs are less effective and it takes as long as 12-24 months to treat a patient with success rate much lower than for drug-sensitive TB. According to various sources between one-third and one-half of patients with TB are infected with HIV, which is associated with very poor prognosis and high mortality. Treatment of TB patients with HIV co-infection is a challenging task. Despite the overwhelming burden of disease, no new anti-TB compounds were developed in last 40 years and current strains of TB are becoming increasingly resistant to existing drugs. At least 10% of TB cases are now drug-resistant forms. The treatment of TB, refractory to conventional ATT, requires the deployment of second line TB drugs. This represents a significant challenge, particularly in resource-poor countries, since the cost of the therapy increases 100-fold. It is clear that alternative and improved treatment options are needed. If such an intervention is found, the impact on the healthcare and clinical management of treatment-refractory, i.e., drug-resistant TB or relapsed TB and/or TB-HIV patients will be tremendous. The significant efforts are directed at finding new drugs and vaccines against TB. Immune-based interventions are actively sought as an adjunct therapy to conventional ATT.
The vaccine against TB was introduced in 1921 and consists of live Bacille Calmette Guerin (BCG)—a form of mycobacterium originally derived from M. bovis. BCG can reduce the risk of severe TB in young children but it is not very effective in preventing pulmonary TB in adolescents and adults, which are the populations with the highest rates of the disease. As BCG is not effective in these circumstances there are many attempts to develop better BCG-based recombinant vaccines (e.g. U.S. Pat. No. 5,830,475). BCG usually comes in injectable forms and is thus problematic for a widespread use, requiring specialized skills for delivery. Live BCG is also used as an oral vaccine. This is Brazilian liquid BCG vaccine, made by Fundação Ataulpho de Paiva (Brazilian League Against Tuberculosis) in Rio de Janeiro. It consists of unique ‘Moreau Rio de Janeiro’ strain of BCG. The strain has been established and used in Brazil for over 70 years. The effect of such oral vaccines is not predictable due to the potential danger of mycobacterium to revert to a virulent form, that can then cause the disease. Another unpredictable parameter recognized by those skilled in the art is that on passage to the stomach, the vaccine antigenic component(s) are rapidly inactivated by the gastric pH and digestive enzymes, and thus systemic assimilation through the gut wall is poor or non-existent.
TB vaccines were equally tried as therapeutic modalities for more than 100 years. Back in 1890, Robert Koch, the discoverer of Mycobacterium tuberculosis, had announced that the injection of tuberculin can cure the disease. However, the subsequent clinical trial involving nearly 2,000 patients revealed that only 2% benefited from this approach. There are reports of use of BCG as an adjunct to TB therapy. In a Chinese study involving 360 volunteers with TB, the negative sputum conversion rate in BCG recipients was 98.3% and 97.2% in chemotherapy control. While this was not significant, the recurrence of TB after 5 years in BCG group was 2.3%, but 6.9% in control group. In contrast, when therapeutic vaccination with BCG was attempted in a mouse model, it resulted in an exacerbation of the disease—a phenomenon first observed by Koch.
The therapeutic vaccine that has shown more promise is a killed Mycobacterium vaccae preparation which was discovered and developed by John Stanford (U.S. Pat. No. 4,724,144). This immunotherapy has been tested in many countries worldwide and usually resulted in a better outcome than chemotherapy alone. For example, negative sputum conversion seen in MDR-TB patients after 3 months was 43%, while among those who received chemotherapy was 21%. M. vaccae appeared to produce a measurable improvement in some geographical regions, but not in others, suggesting that different environmental and immunological experiences of the treated host can contribute to this inconsistency. Recently, a therapeutic vaccine, RUTI, containing detoxified cellular fragments of M. tuberculosis, was reported, but no data regarding its efficacy in humans is yet available, although in animals this vaccine has shown promising results. Other mycobacterium species were employed in attempt to treat TB. These included M. phlei and M. w (a vaccine originally developed for leprosy). Again, the clinical outcome in TB patients was modest and unpredictable. Due to potential risk of inducing a Koch-like reaction, there is a consensus among those skilled in the art that extreme caution is needed in order to develop safe and effective post-exposure vaccines.
Thus, there remains a long-felt need for better therapies or a vaccine. Such therapies additionally need to be free of undesirable properties, such as patient toxicity or even death, the inducement of drug resistance, and the requirement of complicated routes or means of delivery. While many promising vaccines were claimed to be successful in animal models, as a rule, they were not proven be effective and safe in humans. Thus, it is not obvious whether one will be able to develop an effective TB vaccine.
Currently 13 new candidate vaccines have entered clinical trials in humans and over 40 are in the pipeline. The overwhelming majority, if not all of these vaccines, are planned to be administered by injection because it is generally believed that oral administration of a vaccine leads to its destruction in the digestive tract. Thus, none of the present strategies teach, disclose, or suggest an oral composition comprising mycobacterial pathogen or a plurality of antigens of a pathogen or a fragment of a mycobacterial antigen along with an alloantigen.